Fibroblasts infected with most low-passage clinical isolates of human cytomegalovirus (CMV) were as susceptible to lysis by human natural killer (NK) cells as high passage AD-169-infected fibroblasts. NK lysis occurred despite the absence of detectable CMV-specific late membrane antigen(s) on the majority of the target cells infected with most of the low passage strains. The magnitude of NK lysis of different CMV-infected target cells did not correlate with their ability to induce IFN-alpha. NK cell-mediated lysis of cells infected with low-passage clinical isolates of CMV required both NK cells and HLA-DR+ accessory cells, as previously shown for AD-169-infected target cells.